Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is not curable with current therapies. While chemo immunotherapy has improved survival in CLL, all patients eventually relapse, and treatment options for relapsed disease are limited. Additionally, potential for deleterious clonal evolution, treatment related myeloid neoplasia, and immune suppression induced by chemotherapy are major limitations of these therapies. Our group is focused on developing non-chemotherapy-based treatments for CLL, and has been instrumental in the preclinical work, clinical trials, and FDA approval associated with the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib. The success with this agent has been extraordinary, and resistance mechanisms recently identified by our group in collaboration with others has validated this target and the B-cell receptor signaling pathway in this disease. While ibrutinib has phenomenal activity, it also has considerable off-target activity which may be responsible for toxicity, and the inhibition of ITK diminishes the potential for combination with CD20 monoclonal antibodies. In this proposal, we attempt to improve BTK inhibition by investigating a more selective BTK inhibitor ACP-196. We will characterize this molecule pre-clinically in primary CLL cells and also investigate this drug in vitro in combination with CD20 monoclonal antibodies. In parallel, we will conduct a phase Ib trial of ACP-196 plus obinutuzumab in CLL, which will include a safety cohort in relapsed as well as treatment-nave disease and expansion to evaluate efficacy in these patient groups. In our third aim, we will explore alternative targeted agents for patients who relapse on ibrutinib through the development of BTK C481 mutations which we have shown is the most common type of resistance with ibrutinib. We will investigate three pathways/targets for which we have preliminary data: alternative BTK targeting with GDC0853, PI3K with IPI- 145, and BCL2 with ABT-199. At the conclusion of this project, we plan to have investigated a novel BTK inhibitor in CLL in both the front-line and relapsed setting and provide preclinical justification for three agents which are hypothesized to be effective in ibrutinib-resistant disease.